The overall goal of the proposed research is to develop evolutionary genetic theory for understanding how co-transmission of host and microbial genomes affects co-evolution between hosts and their symbiotic or pathogenic microbes. Our approach is novel in that it extends theory of the inheritance of nuclear gene combinations within single genomes to gene combinations across two genomes, those of host and symbiont. Two-locus descent theory quantifies the coinheritance of gene combinations, whether in the same or in different genomes: the greater the coinheritance, the greater the degree to which the evolutionary trajectories of both genes are conjoined. Our results will allow us to interpret patterns of trans-genomic co- variation (interspecies disequilibria) in terms of th underlying causal evolutionary processes. We propose that coinheritance determines whether a host-symbiont association evolves toward enhanced virulence or toward benign mutualistic symbiosis. When applied to nuclear and mitochondrial gene combinations, we successfully predicted that the frequency of functional gene transfer from the mitochondria to the nucleus would be a function of the degree of selfing and discovered that inter-genomic transfer of functional genes is ten-fold more likely to occur in inbreeding species than in outcrossing species. Coinheritance of mitochondrial and nuclear genes in selfing mating systems allows selection to act more effectively on gene combinations than mating systems where nuclear and mitochondrial genes are inherited independently. Althoughmitochondria are wholly vertically transmitted like some symbionts, we expect similar effects to be manifest in systems with partial vertical transmission or in systems with contagious transmission of symbionts among host that are genetic relatives. In this proposed research we will address five specific aims which will develop theory to address the 1) generation and maintenance of interspecies disequilibria, 2) functional gene loss or transfer in host-symbiont associations, 3) coevolution of transmission mode, virulence, and population genetic structure. We propose to develop this more general theory, building upon progress from prior NIH funding.